Studying regioisomer formation in the Pd-catalyzed fluorination of aryl triflates by deuterium labeling.

Isotopic labeling has been used to determine that a portion of the desired product in the Pd-catalyzed fluorination of electron-rich, non-ortho-substituted aryl triflates results from direct C-F cross-coupling. In some cases, formation of a Pd-aryne intermediate is responsible for producing undesired regioisomers. The generation of the Pd-aryne intermediate occurs primarily via ortho-deprotonation of a L·Pd(Ar)OTf (L = biaryl monophosphine) species by CsF and thus competes directly with the transmetalation step of the catalytic cycle. Deuterium labeling studies were conducted with a variety of aryl triflates.

Introduction

Fluorinated arenes are prevalent in the pharmaceutical and agrochemical industries due to their desirable metabolic properties.[1] Nonetheless, accessing them remains a significant challenge.[2] Although Pd-catalyzed halide exchange of aryl (pseudo)halides with a metal fluoride salt (F–) would be an efficient route to generate C–F bonds, studies by Grushin[3] and Yandulov[4] revealed that such a reaction would be hampered by a high barrier to reductive elimination from a Pd(II) intermediate and the solvent-dependent nucleophilicity and basicity of metal fluorides. To circumvent these problems, several reactions based on reductive elimination from a Pd(IV) species using electrophilic fluorinating agents (F+) have been developed.[5] To date, only a few transition metal-mediated nucleophilic aryl fluorination reactions have been reported.[2b,6]

In 2009, we reported that a catalyst based on the biaryl phosphine ligand tBuBrettPhos (1) can effect the conversion of aryl triflates to the corresponding aryl fluorides using CsF (Figure 1).[7] Surprisingly, the fluorinations of electron-rich substrates lacking ortho substituents, such as 2-OTf and 3-OTf, yield regioisomeric products 2b and 3b in addition to desired products 2a and 3a (Figure 1). In contrast, electron-deficient (4-OTf) and ortho-substituted substrates (5-OTf) convert cleanly to the desired products 4a and 5a, respectively (Figure 1).[7]

Figure 1

Regioisomer formation in the Pd-catalyzed fluorination of aryl triflates 2–5-OTf and ligands (1, 6) for this process. tol = toluene.

Previous mechanistic investigations of the catalytic fluorination reaction revealed that 3′-arylation of 1 by the substrate, leading to 6, occurs during the fluorination reaction (Figure 1), although this process appears to be independent of regioisomer formation.[8] Importantly, we have found that complex 7a (bearing 3′-arylated ligand 6a) consistently generates regioisomerically pure 4-(nBu)PhF (3a) when heated, albeit in low (15–20%) yield (Figure 2).[8b] Intriguingly, attempting to increase the yield by adding 4-(nBu)PhOTf (3-OTf) to trap the L·Pd(0) species formed after reductive elimination[9] led to regioisomeric mixtures of 3a and 3b (Figure 2).[8b,10] Together, these results confirm that (a) potential catalytic intermediate 7a does not generate significant quantities of regioisomeric 3-(nBu)PhF (3b) on its own and (b) regioisomer formation in the catalytic reaction may not require the presence of basic CsF to occur. We propose that the catalytic cycle shown in Figure 2, involving oxidative addition of the aryl triflate to 8 to form 9, transmetalation with CsF to form 7, and C–F reductive elimination from 7, is a feasible pathway to form aryl fluorides from aryl triflates. Thus, in the case of aryl triflates such as 2-OTf and 3-OTf, a separate pathway must be occurring to generate the regioisomeric products 2b and 3b. In the present work, we provide evidence that the process in Figure 2 occurs to convert 3-OTf to 3a and that the analogous pathway is operative during the fluorination of other aryl triflates. However, in cases where regioisomeric mixtures of products are observed, ortho-deprotonation of L·Pd(Ar)OTf intermediates 9 to generate Pd-aryne intermediates, which recombine with HF to ultimately produce regioisomeric mixtures of aryl fluorides, competes with this process. Although our previously reported stoichiometric studies[8b] show that L·Pd(Ar)F complexes are capable of effecting this ortho-deprotonation process as well, the studies presented herein suggest that CsF is the more likely culprit for this process in the catalytic reaction. By selectively deuterating aryl fluoride products generated from Pd-aryne intermediates, we can estimate the contribution of this pathway to the outcome of catalytic fluorination reactions.

Figure 2

Observed stoichiometric C–F reductive elimination from 7a, with regioisomer formation observed only in the presence of 3-OTf.[8b] The proposed catalytic cycle for the formation of aryl fluorides from aryl triflates. n/o = not observed.

Results and Discussion

Evidence for Pd-Aryne Intermediate

The most straightforward mechanism for regioisomer formation in this reaction involves ortho-deprotonation of the starting material or product(s) by a basic fluoride species without direct involvement of the catalyst. The aryne so generated would lead to both aryl fluoride products by nucleophilic attack of external fluoride at two distinct sites.[11] Because regioisomer formation is not observed in the absence of catalyst, we consider this pathway to be unlikely.[12] A more plausible scenario is ortho-deprotonation of a catalytic intermediate, such as 9 or 7, by an external basic fluoride species to generate a Pd-aryne[13] intermediate such as 10 (Figure 3). The basic fluoride source could be either CsF or a second molecules of 7, as suggested by our previous stoichiometric experiments.[8b,14] The nonselective reaction of 10 with HF would provide regioisomeric L·Pd(Ar)F complexes 7 and 7′,[15] which could, in turn, independently undergo C–F reductive elimination to generate the observed mixture of regioisomeric aryl fluorides a and b. Consistent with this hypothesis, we have reported that the fluorinations of 2,6-dideuterated aryl triflates show improved regioselectivity compared to that of their nondeuterated analogues,[7] suggesting that scission of the C–H bond adjacent to the triflate group occurs before or during the regioselectivity-determining step.[16]

Figure 3

Proposed mechanism of regioisomer formation by deprotonation of 7 or 9 (Figure 2) by CsF or 7 to generate 10, leading to 7 and 7′, which then reductively eliminate to form a and b, respectively.

To investigate the plausibility of this mechanism, we reasoned that the addition of an exchangeable deuterium source to the reaction mixture would form DF in situ, which could recombine with 10 to allow deuterium incorporation into the aryl fluoride products. However, any product resulting from the desired direct C–F reductive elimination pathway outlined in Figure 2 would not show evidence of deuterium incorporation under these conditions. When 1.0 equiv of tBuOD was added to the catalytic fluorination of 3-OTf, 20% deuterium labeling of the aryl fluoride products was detected by GC/MS.[17−19] In addition to the normally observed 19F NMR signals for 3a (30%) and 3b (14%) in the product mixture were two new signals for aryl fluoride species 3c (3%) and 3d (8%) (Figure 4). The structures of these compounds were confirmed by their independent synthesis using the routes in Scheme 1. Compound 3a was prepared from 11 by adapting previously reported conditions for the Balz–Schiemann reaction[20] via diazonium salt 12, which was not isolated. Negishi coupling of 13 with nBuZnCl in the presence of XantPhos-based 2-aminobiphenyl mesylate precatalyst 15(21,22) gave 14, which could be converted to 3c by lithium–halogen exchange with tBuLi followed by quenching with CD3OD at −78 °C. Similar routes were used to prepare 3b and 3d (not shown, see Supporting Information for details). The presence of 3b in the product mixture suggests that deuteration of products originating from 10a was not complete and therefore that some of the desired product 3a likely comes from 10a as well. By assuming that the two sites of 10a are similarly susceptible to deuterium incorporation upon reaction with DF (see Supporting Information for details), we estimate that 5% of the observed 3a comes from the aryne intermediate 10a and the other 25% originates from a pathway for which no deuterium labeling or regioisomer formation is possible. In other words, 56% of the aryl fluoride products likely originate from 10a, and the other 45%, exclusively 3a, likely comes from the desired C–F cross-coupling pathway outlined in Figure 2. This study provides the first tangible evidence that formation of 10a (Figure 3), leading to 3a–b, and C–F cross-coupling (Figure 2), leading only to 3a, are directly competing processes during the catalytic fluorination of 3-OTf.[23]

Figure 4

Addition of tBuOD to the fluorination of 3-OTf leads to 3a–d. The 19F NMR (282 MHz) spectra of the crude product mixture without (top) and with (bottom) tBuOD added are shown. An internal reference of 1-fluoronaphthalene is included.

Scheme 1

Preparation of 3a and 3c

Species Responsible for Pd-Aryne Formation

Kinetic Profiles of Pd-Catalyzed Fluorinations of 1-Naphthyl and 4-(n-Butyl)phenyl Triflates

To determine the kinetic parameters of the two pathways occurring during the fluorination of 3-OTf, it is helpful to compare the Pd-catalyzed fluorinations of 1-naphthyl triflate (16-OTf, Figure 5), which proceeds cleanly to 1-fluoronaphthalene (16e)[24] and thus likely by a pathway analogous to that outlined in Figure 2, with that of 3-OTf, which produces both 3a and 3b. Notably, the addition of tBuOD to the fluorination of 16-OTf did not result in deuterium incorporation into the formed 1-fluoronaphthalene 16e, indicating that competitive Pd-aryne formation is likely not occurring in this case (Figure 5A, see the Ortho Substituent Effects section for discussion). The fluorination of 16-OTf is zeroth order in [ArOTf],[24] nearly first order in [Pd] (k10% Pd/k5% Pd = 1.82 ± 0.18, Figure 5B), and, as we have previously reported, shows a positive order in CsF.[24,25] Thus, the rate law for the desired cross-coupling process (at least in this case) follows rate = k[Pd][CsF] (n > 0). These findings are consistent with L·Pd(1-naphthyl)OTf species 17a or 17b (Figure 5C) being the resting state of the catalyst. Thus, for the desired cross-coupling reaction, the resting state of the catalyst is likely a L·Pd(Ar)OTf species (L = 1 or 6), and either transmetalation or reductive elimination is the rate-determining step of the catalytic cycle.[26]

Figure 5

Analysis of the Pd-catalyzed fluorination of 16-OTf, which proceeds cleanly to 16e. (A) No deuterium incorporation to form 16f is observed in the presence of tBuOD. (B) Rate of starting material consumption during the fluorination of 16-OTf with 5% Pd (blue diamonds) or 10% Pd (red squares). Conversions determined by GC analysis. (C) The resting state of the catalyst during the catalytic fluorination reaction is likely 17a or 17b.

The fluorination of 3-OTf shows many of the same features as those of 16-OTf (Figure 6). We have previously shown that the reaction is zeroth order in aryl triflate.[8b] Indeed, the growth of both products over time is linear (Figure 6A), with the relative rates for their formation (k/k = 1.67 ± 0.34) approximately equal to the final observed regioselectivity (3a/3b ≈ 1.7:1). This finding is consistent with our hypothesis that formation of the undesired regioisomer 3b occurs competitively with formation of 3a and suggests that both products ultimately originate from the same intermediate. In addition, the rate of starting material consumption during the Pd-catalyzed fluorination of 3-OTf shows a nearly identical dependence on [Pd] (k10% Pd/k5% Pd = 1.71 ± 0.18, Figure 6B) as that for the reaction of 16-OTf (k10% Pd/k5% Pd = 1.82 ± 0.18, Figure 5B). This finding suggests that the rate dependence on [Pd] of the pathways occurring during the fluorination of 3-OTf is nearly equal, as otherwise this reaction would show a different rate dependence on [Pd] than the fluorination of 16-OTf (vide infra). Indeed, when the catalytic fluorination of 3-OTf was conducted using varying amounts of [(cinnamyl)PdCl]2 (2.50–10.0%) and 1 (3.75–15.0%) while maintaining the 1:1.5 ratio of Pd/1, no significant change in the extent of deuterium incorporation was observed (see Supporting Information Table S3a). Likewise, changing the amount of 1 (5.00–10.0%) while holding the quantity of [(cinnamyl)PdCl]2 constant (Supporting Information Table S3b) or conducting the same experiment using varying amounts of 9a (5.00–10.0%) (Supporting Information Table S3c) showed no significant dependence of regioselectivity or the percent aryne on catalyst or ligand loading.

Figure 6

Analysis of the Pd-catalyzed fluorination of 3-OTf. (A) The growth of 3a (blue diamonds) and 3b (red squares) during the catalytic fluorination of 3-OTf. Yields were determined by 19F NMR (282 MHz). (B) Rate of starting material consumption during the fluorination of 3-OTf with 3.0 equiv CsF, 5% Pd (blue diamonds); 3.0 equiv CsF, 10% Pd (red squares); and 1.5 equiv CsF, 5% Pd (green circles). Conversions were determined by GC analysis.

Similar to the results previously reported for the fluorination of 16-OTf,[24] the Pd-catalyzed fluorination of 3-OTf displays a small but statistically significant positive order in [CsF] (k3equiv CsF/k1.5equiv CsF = 1.24 ± 0.09, Figure 6B).[27] The observed zeroth order dependence on [ArOTf] but positive order in [CsF] suggests that 9a is likely the resting state of the catalyst during this reaction. Additionally, low-temperature 19F NMR (470 MHz, −78 °C) studies of the catalytic fluorination reaction of 3-OTf run to partial conversion (see Supporting Information Figure S2), support that 9a is the resting state of the catalyst, with 7a present in too low of a concentration to be reliably observed.[28] From all of the experiments we have conducted to date, we can reliably conclude that (a) the resting state of the catalyst in these reactions is a L·Pd(Ar)OTf species, (b) regioisomer formation and the desired cross-coupling reaction show a similar rate dependence on [Pd], (c) both reactions show a positive, nonlinear dependence on [CsF], and (d) ortho-deprotonation is the rate-determining step of regioisomer formation (vide supra). On the basis of these conclusions, we next investigated which species were directly involved in Pd-aryne formation during the catalytic fluorination of 3-OTf.

Species Undergoing Ortho-Deprotonation

We initially hypothesized that 9a is the major species undergoing ortho-deprotonation competitively with transmetalation because (a) 9a is the resting state of the catalyst and so is present in a much higher concentration than 7a, (b) the protons in 9a adjacent to the cationic Pd center should be more acidic than the corresponding protons in 7a, and (c) in our previously reported stoichiometric reductive elimination experiments with 7a (Figure 2), regioisomer formation was observed only when 3-OTf was added to trap the L·Pd(0) species formed after reductive elimination from 7a.[8b,29] In addition, the lack of multiply deuterated products in the product mixture is consistent with ortho-deprotonation of 9a instead of 7a. The deprotonation of 9a to form 10a should be irreversible because the reverse process would require three species, namely, 10a, HF, and CsOTf, to react together in the transition state.[30] Thus, if 7a (and the corresponding meta-substituted isomer 7a′) cannot be deprotonated during the catalytic reaction, then only one deuterium incorporation event could take place before formation of the desired aryl fluorides, leading to 3a–d. However, if ortho-deprotonation of 7a (or 7a′) in competition with reductive elimination were possible, then multiple deuterium atoms could be incorporated into the aryl fluoride products. The lack of multiply deuterated products is consistent with the reaction of 10a with HF being irreversible. In other words, ortho-deprotonation of 7a likely does not directly compete with reductive elimination.[31,32]

F– Source Involved in Pd-Aryne Formation

We also investigated whether CsF or 7a was more likely to be the base responsible for Pd-aryne formation. Although significantly more CsF (∼40–60 equiv relative to 9a) is present than 7a during the catalytic reaction, our previous stoichiometric studies corroborate that 7a is capable of deprotonating 9a.[8b,29] Our kinetic studies with 16-OTf suggest that the rate law of the desired cross-coupling process is rate = k[Pd][CsF] (n > 0). In addition, the improved regioselectivity observed with 2,6-dideuterated substrates suggests that ortho-deprotonation occurs before or during the rate-limiting step of regioisomer formation.[7] If rate-limiting ortho-deprotonation involved one molecule of 7a reacting with a molecule of 9a, then the rate of ortho-deprotonation would follow rate = k[Pd]2. In this case, the extent of regioisomer formation and percentage of aryne would increase with catalyst loading, as the rate of ortho-deprotonation would be greatly accelerated over that of cross-coupling. However, if ortho-deprotonation involved deprotonation of 9a by CsF, then the rate of ortho-deprotonation would follow rate = k[Pd][CsF] (m > 0; m and n are not necessarily equal). In this case, increasing the catalyst loading would equally raise the rate of the competing cross-coupling process (Figure 2) and Pd-aryne formation (Figure 3), resulting in no change in regioselectivity at higher catalyst loadings. As we previously showed (Kinetic Profiles of Pd-Catalyzed Fluorinations of 1-Naphthyl and 4-( section), changing the catalyst loading of the Pd-catalyzed fluorination of 3-OTf does not affect the regioselectivity or percent aryne of the reaction (see Supporting Information Table S3a,c). These results suggest that regioisomer formation and the pathway shown in Figure 2 have the same rate dependence on [Pd]. This result is consistent with CsF, not a L·Pd(Ar)F intermediate, acting as the base responsible for ortho-deprotonation of 9a.[27] Nonetheless, stoichiometric experiments confirm that 7a is capable of reacting with 9a to generate 10a. Therefore, it is likely only the extremely low concentration of 9a present during the catalytic reaction that limits its involvement in regioisomer formation. We cannot entirely rule out that a small portion of the 10a formed during the catalytic reaction comes from ortho-deprotonation of 9a by 7a.

We also investigated the stoichiometric reaction between 9a and CsF to search for evidence of formation of 10a. When CsF (5 equiv) was added to a solution of 9a (1 equiv) in toluene, minimal conversion to 7a was observed, even after 12 h (Table 1, entry 1). This finding is likely due to the poor solubility of CsF in toluene, especially at room temperature. When the CsF/Pd ratio was increased to that found at the beginning of the catalytic reaction (60:1), significant conversion (85%) of 9a occurred in only 0.5 h, but a lower yield of 7a than expected (55% yield relative to an internal standard) was observed (Table 1, entry 2). No other fluorine- or phosphorus-containing species could be detected by NMR, as the generated HF was likely rapidly trapped as CsHF2. However, analysis of the reaction mixture by GC/MS showed unidentified high molecular weight compounds to be present. Thus far, our unsuccessful efforts to isolate 10a (not shown) suggest that it is extremely reactive toward trimerization and oligimerization in solution.[16] Thus, the discrepancy in conversion and yield when 9a is reacted with CsF is indirect evidence that 10a is forming in situ along with 7a.[33] On the basis of these findings, the mechanism shown in Figure 7, involving competitive transmetalation (leading ultimately to a) and deprotonation (leading ultimately to a and b) of a L·Pd(Ar)OTf intermediate with CsF, is the most likely scenario for regioisomer formation in the Pd-catalyzed fluorination of aryl triflates.

Table 1

Stoichiometric Transmetalation Experiments with 12 and CsF in Toluene

entry	CsF equiv	time (h)	conversion (%)	yield (%)
1	5	12	<10	<10
2	60	0.5	85	55

Figure 7

Complex 9 can either undergo transmetalation to yield 7 (Figure 2) and ultimately aryl fluoride a or ortho-deprotonation to yield 10 (Figure 3) and ultimately aryl fluorides a (from 7) and b (from 7′) during the catalytic fluorination reaction.

Para Substituent Effects

We next applied our deuterium labeling protocol to other para-substituted substrates to gain insight into the effect of aryl triflate substitution patterns on the formation and behavior of 10 (Table 2). For each substrate, two Pd-catalyzed fluorinations were conducted: one without tBuOD added to determine the combined yield (a + b)[17] and regioselectivity (a/b) of the reaction and one with tBuOD added to determine the total deuterium incorporation into the aryl fluoride products (% D) and the estimated fraction of aryl fluoride products originating from 10 (% aryne). In a series of para-substituted aryl triflates (Table 2), deuterium incorporation (% D) and percent aryne steadily decrease as the substituent becomes more electron-withdrawing so that electron-deficient aryl fluorides 4a, 21a, and 22a are formed without any corresponding deuterated or regioisomeric products. The observed reactivity of para-substituted aryl triflates is consistent with the mechanistic scenario presented in Figure 7. This is because catalytic intermediates bearing electron-rich aryl groups would undergo slower transmetalation than those bearing electron-deficient aryl groups, providing a greater opportunity for competitive ortho-deprotonation by CsF (or 7) to occur. Notably, multiply deuterated products were not observed in the product mixtures for these para-substituted substrates, consistent with our hypothesis that conversion of 10 to 7 is irreversible.[32]

Table 2

Effect of Para-Substituents on Fluorination

substrate	R	combined % yield (a + b)a,[17]	para:meta (a:b)a	a:c:b:db	% Db	% aryneb
3-OTf	nBu	70	1.5:1	30:3:14:8	20 ± 1	56 ± 3
18-OTf	H	61	n/a	51:10	16 ± 1	16−33c
19-OTf	Ph	75	8.5:1	66:5:5:5	12 ± 1	25 ± 3
20-OTf	Cl	37	7.8:1	31:2:2:2	11 ± 1	20 ± 3
21-OTf	CO2Me	94	>99:1	94:n/o:n/o:n/o	<1	<1
4-OTf	CN	80	>99:1	80:n/o:n/o:n/o	<1	<1
22-OTf	NO2	80	>99:1	80:n/o:n/o:n/o	<1	<1

On a 0.2 mmol scale; reactions without tBuOD added. 19F NMR yields.

On a 0.2 mmol scale; reactions with tBuOD added. 19F NMR yields.

Estimated range assuming that between 0% of 18a (16% aryne) and 10% of 18a (33% aryne) originates from 10. n/o = not observed.

We have previously reported that Pd-catalyzed fluorination reactions conducted in cyclohexane instead of toluene result in improved regioselectivity for formation of the desired product.[7] However, using cyclohexane as the reaction solvent typically requires higher temperatures and/or catalyst loadings, presumably due to the even lower solubility of CsF in cyclohexane compared to toluene.[34] As the results in Table 3 show, for 3-OTf and 19-OTf more of the aryl fluoride product a originates from the desired cross-coupling process (Figure 2) and less from Pd-aryne 10 (Figure 3), leading to an improved regioselectivity for the desired products 3a and 19a, respectively.[35] Notably, the fluorination reactions of substrates with more electron-withdrawing para substituents proceed to a single regioisomer of product in cyclohexane as well as in toluene (not shown). The two most likely explanations for increased regioselectivity in cyclohexane are (1) less of Pd-aryne 10 is forming in cyclohexane or (2) 10 forms to an equal degree in both solvents but is converted into non-fluorine-containing side products, such as aryne-derived trimers[16] or oligomers, instead of aryl fluoride products, in cyclohexane. Because the overall yields for the reactions in Table 3 are close to those in Table 2 and no increase in potential aryne-derived byproducts occurs in cyclohexane, the second explanation is unlikely. Thus, switching the solvent to cyclohexane likely slows ortho-deprotonation more than it does transmetalation, leading to the observed increase in regioselectivity. The reason for this change remains unclear, although a subtle change in the nature of the reaction occurring between 9 and the surface of CsF nanoparticles is the most likely explanation. Nonetheless, switching to the nonpolar solvent cyclohexane has the general benefit of decreasing the amount of aryl fluorides originating from Pd-aryne 10.

Table 3

Deuterium Labeling Results with Cyclohexane as Solvent

substrate	R	combined % yield (a + b)a,[17]	para:meta (a:b)a	a:c:b:db	% Db	% aryneb
3-OTf	nBu	60	5.7:1	30:2:5:4	15 ± 1	33 ± 3
19-OTf	Ph	79	12:1	64:3:2:n/o	4 ± 1	7−12c

On a 0.2 mmol scale; reactions without tBuOD added. 19F NMR yields.

On a 0.2 mmol scale; reactions with tBuOD added. 19F NMR yields.

Estimated range assuming that between 0% of 19a (7% aryne) and 3% of 19a (12% aryne) originates from 10. cy = cyclohexane.

Meta Substituent Effects

In the case of meta-substituted substrates, the desired C–F cross-coupling process (Pathway A, Figure 8) leads to the meta-substituted product b. This pathway could be intercepted at intermediate 9′ by the formation of two Pd-aryne intermediates, either away from R (Pathway B) or toward R (Pathway C) (Figure 8). Deprotonation away from R provides 10, the same intermediate formed by deprotonation of the corresponding para-substituted substrate. Reaction of this intermediate with HF would provide complexes 7′ and 7, leading to the desired product b and the undesired para-substituted regioisomer a, respectively. Deprotonation between the Pd center and R would generate Pd-aryne 10′, which could, in turn, react with HF to form regioisomeric L·Pd(Ar)F complexes 7′ and 7″. Reductive elimination from 7′ and 7″ would produce b and e, respectively (Figure 8). Preliminary isotopic labeling studies suggest that for the majority of meta-substituted substrates all three pathways are operative during the catalytic reaction.[36]

Figure 8

Meta-substituted 9′ can undergo transmetalation to yield 7′ and ultimately aryl fluoride b (Pathway A), and/or ortho-deprotonation to yield 10 (Figure 3) and ultimately products a and b from 7 and 7′, respectively (Pathway B), and/or ortho-deprotonation to yield 10′ and ultimately aryl fluorides b and e from 7′ and 7″, respectively (Pathway C). Ortho-substituted products e are not observed.

Although determination of estimated percent aryne values for reactions of meta-substituted substrates was not possible,[36] we were able to investigate the effect of meta substituents on regioisomer formation (Table 4). Notably, ortho-substituted products e resulting from 7″ (Pathway C, Figure 8) were not observed in any case. With alkyl-substituted substrates 23-OTf (R = nBu) and 24-OTf (R = tBu), small amounts of para-substituted products 23–24a were observed along with the desired meta-substituted products 23–24b, which is consistent with formation of 10 (Pathway B, Figure 8) during the reaction (Table 4). Substrates bearing electron-withdrawing ester (25-OTf), nitrile (26-OTf), and nitro (27-OTf) groups in the meta position also generate meta-substituted products (25–27b) with high regioselectivity over para-substituted aryl fluorides (25–27a) (Table 4).[7] However, the identity of the electron-withdrawing group does not have a significant effect on the yield or extent of regioisomer formation. A different result was observed with OMe (28-OTf) or NMe2 (29-OTf) groups in the meta position (28-OTf): in both cases, only the desired products 28–29b were observed by 19F NMR (Table 4). The absence of para-substituted products in these cases confirms that Pathway B (Figure 8) is not operative. Studies aimed at understanding the mechanistic intricacies of the Pd-catalyzed fluorination of meta-substituted aryl triflates are ongoing in our laboratory. We note that, similar to the results in Table 3, the fluorinations of 24-OTf (R = tBu) and 25-OTf (R = CO2Et) could be carried out in cyclohexane to cleanly provide 24b and 25b, respectively, in high yield, with no evidence of regioisomer formation or deuterium incorporation in the presence of tBuOD (Figure 9).[7]

Table 4

Effect of Meta Substituents on the Outcome of Fluorinationa

substrate	R	combined % yield (b + a)	meta:para (b:a)
23-OTf	nBu	73	14:1
24-OTf	tBu	76	16:1
25-OTf	CO2Et	72	11:1
26-OTf	CN	76	16:1
27-OTf	NO2	75	12:1
28-OTf	OMe	60	>99:1
29-OTf	NMe2	59	>99:1

On a 0.2 mmol scale; reactions without tBuOD added. 19F NMR yields.

Figure 9

Using cyclohexane as the reaction solvent improves the regioselectivity of the fluorinations of 24–25-OTf. cy = cyclohexane.

Ortho Substituent Effects

In the case of ortho-substituted substrates, only one Pd-aryne intermediate, 10′ (Figure 10), could conceivably form by competitive ortho-deprotonation of L·Pd(Ar)OTf complex 9″ (Pathway B, Figure 10) during the desired cross-coupling process (Pathway A, Figure 10). However, as for the fluorination of 16-OTf (Figure 5), meta-substituted regioisomers do not form during the Pd-catalyzed fluorination of any ortho-substituted aryl triflate tested to date (Table 5).[7,24] Indeed, substrates bearing ortho-alkoxy (30-OTf) and alkyl (31-OTf) substituents proceed cleanly to the desired ortho-substituted aryl fluorides without deuterium labeling in the presence of tBuOD (Table 5). Even ortho-substituted substrates bearing an electron-withdrawing group in the meta position (32-OTf) or an electron-donating group in the para position (33-OTf) do not undergo deuterium labeling or regioisomer formation, confirming that ortho substitution overrules substituent patterns that normally result in regioisomer formation and deuterium incorporation (Tables 2 and 4).

Figure 10

Formation of Pd-aryne 10′ from 9″ (Pathway B) does not occur during the Pd-catalyzed fluorination of ortho-substituted aryl triflates (Pathway A).

Table 5

Fluorinations of Ortho-Substituted Aryl Triflates[17]

Because we observed that a L·Pd(Ar)OTf species was the resting state of the catalyst in both the fluorinations of 3-OTf (Figure 5) and 16-OTf (Figure 6), it is likely not a change in resting state or rate-determining step that explains the lack of regioisomer formation in the latter case. In general, we have observed that the Pd-catalyzed fluorinations of ortho-substituted substrates are much faster than those of other substrates (compare Figure 5B with Figure 6B). It is well-known that ortho-substituents accelerate the rate of reductive elimination.[37] This could account for the complete regioselectivity of the reactions in Table 5 if reductive elimination is the rate-determining step of Pathway A (Figure 10) and transmetalation is reversible, as the reaction would rapidly funnel toward the desired product e without allowing for ortho-deprotonation of 9″.[38]

An alternative explanation for the complete regioselectivity of the reactions in Table 5 is that, in an effort to minimize steric interactions between the ortho substituent and the tBu groups of the phosphine ligand, 9″ would likely preferentially adopt a conformation with the R group pointing away from the phosphine ligand (A, Figure 11), as pointing the R group toward the tBu groups would be highly disfavored (B, Figure 11). This conformation would leave the only proton ortho to the Pd center (H*, Figure 11) very close to the bulky phosphine ligand, making deprotonation by CsF difficult.

Figure 11

Shielding effect of tBu groups on the ligand could decelerate ortho-deprotonation of preferred conformer A of 9″; conformer B is disfavored due to steric intereactions between R on the aryl group and the tBu groups on the ligand.

Similarly, increased steric interactions between the bulky phosphine ligand and R in 10′ compared to 9″ could disfavor formation of this high-energy intermediate and thus decelerate the rate of Pd-aryne formation (Pathway B, Figure 10). In short, ortho-substituted aryl triflates are a general class of substrates that show no evidence of deuterium incorporation, suggesting that competitive formation of a Pd-aryne intermediate is not occurring under catalytic conditions.

Conclusions

We have found that deuterium labeling can be used to estimate the amount of Pd-aryne intermediates generated during the catalytic fluorination of a variety of ortho- and para-substituted aryl triflates. Using this method, we have revealed that the transmetalation step of the desired C–F cross-coupling process (Figure 2) likely competes with ortho-deprotonation to form a Pd-aryne intermediate (Figure 3). The substrate classes for which regioisomer formation remains a significant challenge are those bearing electron-donating groups in the para position and those bearing certain electron-donating or -withdrawing groups in the meta position, with no other substituents present. Switching the solvent to cyclohexane can prove to be beneficial in these cases by reducing the extent of products originating from Pd-aryne intermediates.[7] Most importantly, the results herein provide corroborating evidence that the desired C–F cross-coupling pathway outlined in Figure 2 occurs to some degree during the Pd-catalyzed fluorination of all tested aryl triflates. Further work in this area will involve investigating regioisomer formation in the recently reported fluorination of aryl bromides and iodides using AgF,[39] elucidating the behavior of meta-substituted substrates, and designing new catalysts that do not allow for regioisomer formation.